The inflammatory process is an extraordinarily complex process, varying with the cause of inflammation, the site of the inflammation, and the nature of the insult. Numerous different types of leukocytes are attracted to the site where the inflammatory process is initiated. The different leukocytes initiate different biological processes to respond to the insult. While in many situations, the inflammatory response is healthy in destroying a pathogen, in other situations, such as autoimmune diseases and transplantation, the inflammatory response is undesirable. In the latter case, this leads to rejection and loss of the implanted organ, which in most cases will be fatal.
A number of different avenues have been investigated to encourage the retention of allografts. For the most part, these avenues have involved general immunosuppression, using drugs such as cyclosporin and FK506. Extensive efforts have been directed to inducing anergy toward the foreign tissue. Also, the role of various factors has been investigated, where by modulating the level of those factors, the immune response may be diminished. For the most part, the primary approach has been the use of drugs which suppress the entire immune system, therefore leaving the patient vulnerable to adventitious infection.
Because of the restricted availability of donor organs, consideration has been given to using xenografts for temporary maintenance, while an acceptable allogenic organ is identified. The xenografts not only differ as to the MHC, but will also have numerous other epitopes differing from the host. Therefore, additional rejection mechanisms are brought to bear against the xenograft.
Heme oxygenases (HO) are the rate-limiting enzymes that catalyze the conversion of heme to biliverdin, carbon monoxide (CO) and free iron, the first step in the oxidative conversion of heme to bilirubin. Recently, great interest has been placed on the role of heme oxygenase in cellular responses to stress and insult, including ischemic and immunogenic effects. All of the end products of heme degradation, including biliverdin, bilirubin, and CO, are known to modulate immune effector functions. Biliverdin has also been shown to inhibit human complement in vitro. Bilirubin inhibits human lymphocyte responses, including PHA-induced proliferation, IL-2 production, and antibody-dependent and -independent cell-mediated cytotoxicity. In addition, heme oxygenase-I (HO-1) upregulation correlates with increased production of nitric oxide (NO), an important effector molecule involved in inflammation and immune regulation. On the other hand, NO is also known to induce HO-1 expression, while CO directly inhibits nitric oxide synthase (NOS) activity by binding to the heme moiety of the NOS enzyme and thus downregulating NO production. Like NO, CO contributes to endothelium-dependent vasodilation and inhibits platelet aggregation by elevating intracellular cGMP levels. The deleterious effects of hyperoxia are thought to be mediated by reactive oxygen species. Both biliverdin and bilirubin are efficient peroxyl radical scavengers that inhibit lipid peroxidation. Bilirubin scavenges peroxyl radicals as efficiently as α-tocopherol, which is regarded as the most potent antioxidant of lipid peroxidation. On the other hand, oxygen radicals may trigger cascade of antiapoptotic events, including those that involve activation of bcl-2 protooncogene. All these factors point to a complex picture of putative regulatory interactions between the HO system and the host cytokine network set in motion through the biological activity of heme degradation products.
There is a pressing need to find alternative modalities which will enhance and extend transplant survival. These modalities may find use in conjunction with other drugs, where lower levels of other drugs having significant side effects may be used effectively, to reduce the detrimental side effects. Thus, there is substantial interest in developing new approaches to improving transplant outcome, where a drug may act by itself or in conjunction with other drugs.